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Asian Journal of Surgery Dec 2023
Topics: Humans; Female; Breast Neoplasms; Bone Neoplasms; Bibliometrics
PubMed: 37714788
DOI: 10.1016/j.asjsur.2023.08.231 -
Aging Jul 2023Bone metastasis (BM) is one of the main manifestations of advanced breast cancer (BC), causing complications such as pathological fractures, which seriously affects the...
Bone metastasis (BM) is one of the main manifestations of advanced breast cancer (BC), causing complications such as pathological fractures, which seriously affects the quality of life of patients and even leads to death. In our study, a global single-cell landscape of the tumor microenvironment was constructed using single cell RNA sequencing data from BM. BC cells were found to be reduced in the BM, while mesenchymal stem cells (MSCs), Fibroblasts and other cells were significantly more abundant in the BM. The subpopulations of these cells were further identified, and the pathways, developmental trajectories and transcriptional regulation of different subpopulations were discussed. The results suggest that with the development of BM, BC cells were vulnerable to oxidative damage, showing a high level of oxidative stress, which played a key role in cell apoptosis. Fibroblasts were obviously involved in the biological processes (BPs) related to ossification and bone remodeling, and play an important role in tumor cell inoculation to bone marrow and growth. MSC subpopulations were significantly enriched in a number of BPs associated with bone growth and development and oxidative stress and may serve as key components of BC cells homing and adhesion to the ecological niche of BM. In conclusion, our research results describe the appearance of tumor microenvironment cell subpopulations in breast cancer patients, reveal the important role of some cells in the balance of BM bone remodeling and the imbalance of BM development, and provide potential therapeutic targets for BM.
Topics: Humans; Female; Breast Neoplasms; Tumor Microenvironment; Quality of Life; Bone Neoplasms; Bone Marrow Cells; Oxidative Stress
PubMed: 37470685
DOI: 10.18632/aging.204885 -
Annals of Palliative Medicine Nov 2023Radiotherapy is an important treatment modality for pain control in patients with bone metastases. Stereotactic body radiation therapy (SBRT), which allows delivering a... (Review)
Review
A critical appraisal of the four systematic reviews and meta-analysis on stereotactic body radiation therapy versus external beam radiotherapy for painful bone metastases and where we go from here.
Radiotherapy is an important treatment modality for pain control in patients with bone metastases. Stereotactic body radiation therapy (SBRT), which allows delivering a much higher dose per fraction while sparing critical structures compared to conventional external beam radiotherapy (cEBRT), has become more widely used, especially in the oligometastatic setting. Randomized controlled trials (RCTs) comparing the pain response rate of SBRT and cEBRT for bone metastases have shown conflicting results, as have four recent systematic reviews with meta-analyses of these trials. Possible reasons for the different outcomes between these reviews include differences in methodology, which trials were included, and the endpoints examined and how they were defined. We suggest ways to improve analysis of these RCTs, particularly performing an individual patient-level meta-analysis since the trials included heterogeneous populations. The results of such studies will help guide future investigations needed to validate patient selection criteria, optimize SBRT dose schedules, include additional endpoints (such as the time to onset of pain response, durability of pain response, quality of life (QOL), and side effects of SBRT), and better assess the cost-effectiveness and trade-offs of SBRT compared to cEBRT. An international Delphi consensus to guide selection of optimal candidates for SBRT is warranted before more prospective data is available.
Topics: Humans; Bone Neoplasms; Pain; Pain Management; Radiosurgery
PubMed: 37303218
DOI: 10.21037/apm-23-218 -
EBioMedicine Jun 2024Bone metastasis is a common consequence of advanced prostate cancer. Bisphosphonates can be used to manage symptoms, but there are currently no curative treatments...
BACKGROUND
Bone metastasis is a common consequence of advanced prostate cancer. Bisphosphonates can be used to manage symptoms, but there are currently no curative treatments available. Altered tumour cell glycosylation is a hallmark of cancer and is an important driver of a malignant phenotype. In prostate cancer, the sialyltransferase ST6GAL1 is upregulated, and studies show ST6GAL1-mediated aberrant sialylation of N-glycans promotes prostate tumour growth and disease progression.
METHODS
Here, we monitor ST6GAL1 in tumour and serum samples from men with aggressive prostate cancer and using in vitro and in vivo models we investigate the role of ST6GAL1 in prostate cancer bone metastasis.
FINDINGS
ST6GAL1 is upregulated in patients with prostate cancer with tumours that have spread to the bone and can promote prostate cancer bone metastasis in vivo. The mechanisms involved are multi-faceted and involve modification of the pre-metastatic niche towards bone resorption to promote the vicious cycle, promoting the development of M2 like macrophages, and the regulation of immunosuppressive sialoglycans. Furthermore, using syngeneic mouse models, we show that inhibiting sialylation can block the spread of prostate tumours to bone.
INTERPRETATION
Our study identifies an important role for ST6GAL1 and α2-6 sialylated N-glycans in prostate cancer bone metastasis, provides proof-of-concept data to show that inhibiting sialylation can suppress the spread of prostate tumours to bone, and highlights sialic acid blockade as an exciting new strategy to develop new therapies for patients with advanced prostate cancer.
FUNDING
Prostate Cancer Research and the Mark Foundation For Cancer Research, the Medical Research Council and Prostate Cancer UK.
Topics: Male; Prostatic Neoplasms; Humans; Sialyltransferases; Animals; Bone Neoplasms; Mice; N-Acetylneuraminic Acid; Cell Line, Tumor; Disease Models, Animal; Antigens, CD; Polysaccharides; Glycosylation; beta-D-Galactoside alpha 2-6-Sialyltransferase
PubMed: 38772281
DOI: 10.1016/j.ebiom.2024.105163 -
Advanced Science (Weinheim,... Jan 2024Bone metastases are a common cause of suffering in breast and prostate cancer patients, however, the interaction between bone cells and cancer cells is poorly...
Bone metastases are a common cause of suffering in breast and prostate cancer patients, however, the interaction between bone cells and cancer cells is poorly understood. Using a series of co-culture, conditioned media, human cancer spheroid, and organ-on-a-chip experiments, this study reveals that osteocytes suppress cancer cell proliferation and increase migration via tumor necrosis factor alpha (TNF-α) secretion. This action is regulated by osteocyte primary cilia and associated intraflagellar transport protein 88 (IFT88). Furthermore, it shows that cancer cells block this mechanism by secreting transforming growth factor beta (TGF-β), which disrupts osteocyte cilia and IFT88 gene expression. This bi-directional crosstalk signaling between osteocytes and cancer cells is common to both breast and prostate cancer. This study also proposes that osteocyte inhibition of cancer cell proliferation decreases as cancer cells increase, producing more TGF-β. Hence, a positive feedback loop develops accelerating metastatic tumor growth. These findings demonstrate the importance of cancer cell-osteocyte signaling in regulating breast and prostate bone metastases and support the development of therapies targeting this pathway.
Topics: Male; Humans; Osteocytes; Cilia; Prostate; Prostatic Neoplasms; Bone Neoplasms; Transforming Growth Factor beta
PubMed: 37967351
DOI: 10.1002/advs.202305842 -
Journal of Translational Medicine Jan 2024Osteosarcoma is the most common malignant primary bone tumor in infants and adolescents. The lack of understanding of the molecular mechanisms underlying osteosarcoma...
BACKGROUND
Osteosarcoma is the most common malignant primary bone tumor in infants and adolescents. The lack of understanding of the molecular mechanisms underlying osteosarcoma progression and metastasis has contributed to a plateau in the development of current therapies. Endoplasmic reticulum (ER) stress has emerged as a significant contributor to the malignant progression of tumors, but its potential regulatory mechanisms in osteosarcoma progression remain unknown.
METHODS
In this study, we collected RNA sequencing and clinical data of osteosarcoma from The TCGA, GSE21257, and GSE33382 cohorts. Differentially expressed analysis and the least absolute shrinkage and selection operator regression analysis were conducted to identify prognostic genes and construct an ER stress-related prognostic signature (ERSRPS). Survival analysis and time dependent ROC analysis were performed to evaluate the predictive performance of the constructed prognostic signature. The "ESTIMATE" package and ssGSEA algorithm were utilized to evaluate the differences in immune cells infiltration between the groups. Cell-based assays, including CCK-8, colony formation, and transwell assays and co-culture system were performed to assess the effects of the target gene and small molecular drug in osteosarcoma. Animal models were employed to assess the anti-osteosarcoma effects of small molecular drug.
RESULTS
Five genes (BLC2, MAGEA3, MAP3K5, STC2, TXNDC12) were identified to construct an ERSRPS. The ER stress-related gene Stanniocalcin 2 (STC2) was identified as a risk gene in this signature. Additionally, STC2 knockdown significantly inhibited osteosarcoma cell proliferation, migration, and invasion. Furthermore, the ER stress-related gene STC2 was found to downregulate the expression of MHC-I molecules in osteosarcoma cells, and mediate immune responses through influencing the infiltration and modulating the function of CD8+ T cells. Patients categorized by risk scores showed distinct immune status, and immunotherapy response. ISOX was subsequently identified and validated as an effective anti-osteosarcoma drug through a combination of CMap database screening and in vitro and in vivo experiments.
CONCLUSION
The ERSRPS may guide personalized treatment decisions for osteosarcoma, and ISOX holds promise for repurposing in osteosarcoma treatment.
Topics: Adolescent; Animals; Humans; Prognosis; Osteosarcoma; Antineoplastic Agents; Algorithms; Bone Neoplasms; Protein Disulfide Reductase (Glutathione)
PubMed: 38229155
DOI: 10.1186/s12967-023-04794-0 -
PloS One 2023Patients with osteosarcoma and synchronous lung metastasis (SLM) have poor survival. This study aimed to explore the epidemiology data and construct a predictive... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with osteosarcoma and synchronous lung metastasis (SLM) have poor survival. This study aimed to explore the epidemiology data and construct a predictive nomogram to identify cases at risk of SLM occurrence among pediatric and young adulthood osteosarcoma patients.
METHODS
All data were extracted from Surveillance, Epidemiology, and End Results 17 registries. The age-standardized incidence rate (ASIR) and annual percentage change was evaluated, and reported for the overall population and by age, gender, race, and primary site. Univariate and multivariate logistic regression analyses were used to identify risk factors associated with SLM occurrence, then significant factors were used to develop the nomogram. The area under the receiver operating characteristic curve (AUC) and calibration curve were used to evaluated the predictive power of the nomogram. Survival analysis was assessed by the Kaplan-Meier method and the log-rank test. Multivariate Cox analysis was used to determine the prognostic factors.
RESULTS
A total of 278 out of 1965 patients (14.1%) presented with SLM at diagnosis. The ASIR increased significant from 0.46 to 0.66 per 1,000,000 person-years from year 2010 to 2019, with an annual percentage change of 3.5, mainly in patients with age 10-19 years, male and appendicular location. All patients were randomly assigned into train cohort and validation cohort with a spilt of 7:3. In the train cohort, higher tumor grade, bigger tumor size, positive lymph nodes and other site-specific metastases (SSM) were identified as significant risk factors associated with SLM occurrence. Then a nomogram was developed based on the four factors. The AUC and calibration curve in both train and validation cohorts demonstrated that the nomogram had moderate predictive power. The median cancer-specific survival was 25 months. Patients with age 20-39 years, male, positive lymph nodes, other SSM were adverse prognostic factors, while surgery was protective factor.
CONCLUSIONS
This study performed a comprehensive analysis regarding pediatric and young adulthood osteosarcoma patients had SLM. A visual, clinically operable, and easy-to-interpret nomogram model was developed for predicting the risk of SLM, which could be used in clinic and help clinicians make better decisions.
Topics: Humans; Child; Male; Young Adult; Adult; Adolescent; Nomograms; Osteosarcoma; Lung Neoplasms; Ambulatory Care Facilities; Bone Neoplasms
PubMed: 37437020
DOI: 10.1371/journal.pone.0288492 -
European Radiology Sep 2023To develop and validate a deep learning (DL) model based on CT for differentiating bone islands and osteoblastic bone metastases.
OBJECTIVE
To develop and validate a deep learning (DL) model based on CT for differentiating bone islands and osteoblastic bone metastases.
MATERIALS AND METHODS
The patients with sclerosing bone lesions (SBLs) were retrospectively included in three hospitals. The images from site 1 were randomly assigned to the training (70%) and intrinsic verification (10%) datasets for developing the two-dimensional (2D) DL model (single-slice input) and "2.5-dimensional" (2.5D) DL model (three-slice input) and to the internal validation dataset (20%) for evaluating the performance of both models. The diagnostic performance was evaluated using the internal validation set from site 1 and additional external validation datasets from site 2 and site 3. And statistically analyze the performance of 2D and 2.5D DL models.
RESULTS
In total, 1918 SBLs in 728 patients in site 1, 122 SBLs in 71 patients in site 2, and 71 SBLs in 47 patients in site 3 were used to develop and test the 2D and 2.5D DL models. The best performance was obtained using the 2.5D DL model, which achieved an AUC of 0.996 (95% confidence interval [CI], 0.995-0.996), 0.958 (95% CI, 0.958-0.960), and 0.952 (95% CI, 0.951-0.953) and accuracies of 0.950, 0.902, and 0.863 for the internal validation set, the external validation set from site 2 and site 3, respectively.
CONCLUSION
A DL model based on a three-slice CT image input (2.5D DL model) can improve the prediction of osteoblastic bone metastases, which can facilitate clinical decision-making.
KEY POINTS
• This study investigated the value of deep learning models in identifying bone islands and osteoblastic bone metastases. • Three-slice CT image input (2.5D DL model) outweighed the 2D model in the classification of sclerosing bone lesions. • The 2.5D deep learning model showed excellent performance using the internal (AUC, 0.996) and two external (AUC, 0.958; AUC, 0.952) validation sets.
Topics: Humans; Bone Neoplasms; Deep Learning; Joint Diseases; Retrospective Studies; Tomography, X-Ray Computed
PubMed: 37060446
DOI: 10.1007/s00330-023-09573-5 -
Cancer Letters Nov 2023Bone metastatic disease of prostate cancer (PCa) is incurable and progression in bone is largely dictated by tumor-stromal interactions in the bone microenvironment. We...
Bone metastatic disease of prostate cancer (PCa) is incurable and progression in bone is largely dictated by tumor-stromal interactions in the bone microenvironment. We showed previously that bone neutrophils initially inhibit bone metastatic PCa growth yet metastatic PCa becomes resistant to neutrophil response. Further, neutrophils isolated from tumor-bone lost their ability to suppress tumor growth through unknown mechanisms. With this study, our goal was to define the impact of metastatic PCa on neutrophil function throughout tumor progression and to determine the potential of neutrophils as predictive biomarkers of metastatic disease. Using patient peripheral blood polymorphonuclear neutrophils (PMNs), we identified that PCa progression dictates PMN cell surface markers and gene expression, but not cytotoxicity against PCa. Importantly, we also identified a novel phenomenon in which second generation androgen deprivation therapy (ADT) suppresses PMN cytotoxicity via increased transforming growth factor beta receptor I (TβRI). High dose testosterone and genetic or pharmacologic TβRI inhibition rescued androgen receptor-mediated neutrophil suppression and restored neutrophil anti-tumor immune response. These studies highlight the ability to leverage standard-care ADT to generate neutrophil anti-tumor responses against bone metastatic PCa.
Topics: Male; Humans; Prostatic Neoplasms; Receptors, Androgen; Androgens; Neutrophils; Androgen Antagonists; Bone Neoplasms; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37940068
DOI: 10.1016/j.canlet.2023.216468 -
BMC Medical Genomics Aug 2023Osteosarcoma, as the most common primary bone malignancy, is urgent to be well-studied on the biomarkers and therapeutic targets to improve the five-year survival rate....
Integration of single-cell sequencing and bulk expression data reveals chemokine signaling pathway in proliferating cells is associated with the survival outcome of osteosarcoma.
BACKGROUND
Osteosarcoma, as the most common primary bone malignancy, is urgent to be well-studied on the biomarkers and therapeutic targets to improve the five-year survival rate. Transcriptomic analysis using single-cell RNA or bulk RNA sequencing has been developed to detect biomarkers in various cancer types.
METHODS AND RESULTS
We applied Scissor to combine single-cell RNA-seq data and bulk transcriptome data of osteosarcoma, providing cell-level information and sample phenotypes to identify the survival-associated cell subpopulations. By investigating the differences between the survival-associated cell subpopulations, we identified CCL21, CCL22, CCL24, CXCL11, CXCL12, CXCL13, GNAI2, and RAC2 in the proliferating cells that are significantly associated with osteosarcoma patient outcome. Then we assigned the risk score for each sample based on the cell proportion-normalized gene expression and validated it in the public dataset.
CONCLUSIONS
This study provides the clinical insight that chemokine signaling pathway genes (CCL21, CCL22, CCL24, CXCL11, CXCL12, CXCL13, GNAI2, and RAC2) in proliferating cells might be the potential biomarkers for treatment of osteosarcoma.
Topics: Humans; Osteosarcoma; Bone Neoplasms; Transcriptome; Biomarkers; Signal Transduction
PubMed: 37537613
DOI: 10.1186/s12920-023-01617-5